Project Summary Alzheimer?s disease (AD) is the principal cause of dementia in the US, and is a pressing public health concern. Currently, treatment options for AD only help relieve AD symptoms without being able to halt or reverse disease progression. Thus, new strategies that can treat AD are urgently needed. Tau protein plays pivotal roles in AD, with the oligomeric form of Tau known to be highly toxic to neuronal cells. In this project, active immunization strategies will be developed to target Tau. In aim 1, a powerful carrier, i.e., bacteriophage Q?, will be developed to conjugate with a pathological Tau peptide epitope to induce antibodies reducing the propensity of Tau to aggregate. Head to head comparison will be performed against one of the most advanced Tau vaccine clinical candidate to demonstrate that the Q? based construct is more superior in eliciting anti-Tau IgG antibodies to reduce oligomeric Tau formation. In aim 2, bacteriophage Q? based vaccine will be constructed to directly target Tau oligomers. This vaccine will induce high levels of IgG antibodies against Tau oligomers, mitigate their toxicities, and protect the neuronal cells from Tau induced death. When successfully developed, this work will lay the necessary ground and provide important leads for the development of vaccines to prevent and treat AD.